PEX3
protein-codingperoxisomal biogenesis factor 3, the group of Peroxins
Gene summary
The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~39.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013948
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013948
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: ClinGen
The relationship between PEX3 and peroxisome biogenesis disorder (types 10A and 10B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 19, 2019. PEX3 encodes a peroxisome membrane protein involved in early peroxisome membrane biosynthesis prior to matrix protein import. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX3 belongs to complementation group G and mutations in the gene result in cells devoid of peroxisomal remnants (Waterham and Ebberink 2012, PMID 22871920). PEX3 was FIRST reported in relation to autosomal recessive Peroxisome biogenesis disorder in 2000. (Muntau et al, PMID: 10958759; Shimozawa et al, PMID: 10942428; Ghaedi et al, PMID: 10968777). At least 8 nonsense, splice site, frameshift and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 8 publications (PMIDs 10958759, 27557811, 28673549, 23245813, 10968777, 10942428, 20033294, 21031596). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is expected to be homozygous loss of function. Summary of experimental data (4.5 points): This gene-disease association is supported by in vitro functional assays and animal models (PMIDs 10958759, 21826223, 12096124). In summary, PEX3 is definitively associated with autosomal recessive Peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on Nov 1, 2019 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0054549
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019609
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013948
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PEX3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003630.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 81 | 85 | |||
| missense | 6 | 137 | 4 | 147 | ||
| nonsense | 8 | 4 | 1 | 13 | ||
| start loss | 1 | 1 | ||||
| frameshift | 9 | 3 | 1 | 13 | ||
| splice donor/acceptor (+/-2bp) | 1 | 10 | 1 | 12 | ||
| Total | 18 | 24 | 144 | 85 | 0 | 271 |
Highest pathogenic variant AF is 0.000017793545
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003621.1 | 12 | MANE Select | |
| Ensembl | ENSP00000356563.4 | 12 | MANE Select | |
| Ensembl | ENSP00000356564.1 | 7 | Standard | |
| Ensembl | ENSP00000588472.1 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Peroxisome - Homo sapiens (human)
- ABC transporters in lipid homeostasis
- Transport of small molecules
- ABC-family proteins mediated transport
Biological Process
- peroxisome organization
- peroxisome membrane biogenesis
- protein import into peroxisome membrane
- transmembrane transport
Molecular Function
- protein binding
- lipid binding
- protein binding, bridging
- protein dimerization activity
Cellular Component
- nucleoplasm
- peroxisome
- peroxisomal membrane
- integral component of peroxisomal membrane
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367591
- Coding exons
- 12
- Length
- 39204
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 26
- Defined
- 125748
- p
- 0.000103
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.19 | 145 | 191 | 0.759 | 0.00000890 | 2439 |
| Missense (PolyPhen) | 37 | 64.308 | 0.57536 | 846 | ||
| Synonymous | 0.703 | 60 | 67.3 | 0.891 | 0.00000317 | 695 |
| Loss of Function | 3.26 | 8 | 25.9 | 0.309 | 0.00000153 | 276 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in peroxisome biosynthesis and integrity. Assembles membrane vesicles before the matrix proteins are translocated. As a docking factor for PEX19, is necessary for the import of peroxisomal membrane proteins in the peroxisomes. {ECO:0000269|PubMed:10848631, ECO:0000269|PubMed:15007061}.;
- Disease
- DISEASE: Peroxisome biogenesis disorder 10A (PBD10A) [MIM:614882]: A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life. {ECO:0000269|PubMed:10848631, ECO:0000269|PubMed:10958759}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 10B (PBD10B) [MIM:617370]: A moderately severe peroxisome biogenesis disorder belonging to the Zellweger disease spectrum. PBD10B is characterized by neonatal jaundice, dysmorphic features, delayed psychomotor development, axial hypotonia that can progress to severe spastic paraparesis with hyperreflexia, nephrocalcinosis, neurogenic bladder, nystagmus, and cataracts. Laboratory studies show increased levels of very long-chain fatty acids. Inheritance is autosomal recessive. {ECO:0000269|PubMed:27557811}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.249
Intolerance Scores
- LoFtool
- 0.593
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.12
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.731
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |